Use of salicylic acid for regulating skin wrinkles and/or skin atrophy

ABSTRACT

The present invention relates to a method for regulating wrinkles and/or atrophy in mammalian skin comprising treating the skin with a safe and effective amount of salicylic acid and/or additional active component.

This is a continuation of application Ser. No. 08/434,250, filed on May3, 1995, which is a continuation of application Ser. No. 08/028,756,filed on Mar. 9, 1993, which is a continuation of application Ser. No.07/796,750, filed on Nov. 25, 1991 all abandoned.

TECHNICAL FIELD

The present invention relates to the field of anti-aging of skin.Specifically, the invention relates to novel methods for effacing andpreventing wrinkles in mammalian skin.

BACKGROUND OF THE INVENTION

Skin is subject to abuse by many extrinsic (environmental) factors aswell as intrinsic (chronoaging) factors. A common extrinsic factor isexposure to ultraviolet radiation. Whether extrinsic or intrinsic, theabuse results in wrinkling of the skin. To many people, skin wrinklesare a reminder of the disappearance of youth. As a result, theelimination of wrinkles has become a booming business in youth-conscioussocieties. Treatments range from cosmetic creams and moisturizers tovarious forms of cosmetic surgery.

Chronoaging results in the thinning and general degradation of skin. Asthe skin naturally ages, there is a reduction in the cells and bloodvessels that supply the skin. There is also a flattening of thedermal-epidermal junction which results in weaker mechanical resistanceof this junction. As a consequence, older persons are more susceptive toblister formation in cases of mechanical trauma or disease processes.(See Oikarinen, (1990) "The Aging of Skin: Chronoaging VersusPhotoaging", Photodermatal. Photoimmunol. Photomed., Vol. 7, pp 3-4).

It is known to use salicyclic acid for the treatment of acne, see forexample, U.S Pat. Nos. 4,891,227 and 4,891,228, to Thaman et al., bothissued Jan. 2, 1990 the disclosures of which are incorporated herein.Further, salicylic acid has been used for the removal of wart, corns andcalluses; for the treatment of psoriasis, seborrheic dermatitis anddandruff; and for the topical treatment of ringworm infection. A listingof commercially available products containing salicylic acid will befound in the Physician's Desk Reference, 45th Edition, 1991, page 323.However, these prior art uses of salicylic acid have generally involvedshort term treatments in which relatively large doses of the acid areapplied (i.e., sufficient to cause significant irritation and oftenpeeling) in order to obtain a cure or treatment of the particularcondition, such as removal of comedones, as opposed to persistenttreatment of normal aging skin.

OBJECTS OF THE PRESENT INVENTION

It is an object of the present invention to provide a method ofregulating wrinkles and/or atrophy in mammalian skin which comprisestreating mammalian skin with a safe and effective amount of ananti-wrinkle/anti-atrophy agent.

SUMMARY OF THE INVENTION

The present invention relates to a method for regulating wrinkles and/oratrophy in mammalian skin comprising chronic treatment of the skin witha safe and effective amount of salicylic acid.

All percentages and ratios used herein are by weight and allmeasurements are at 25° C. unless otherwise indicated.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, "alkyl" means an unsubstituted carbon-containing chainwhich may be straight, branched or cyclic, preferably straight orbranched, more preferably straight; saturated, monounsaturated (i.e.,one double or triple bond in the chain), or polyunsaturated (i.e., twoor more double bonds in the chain; two or more triple bonds in thechain; one or more double and one or more triple bonds in the chain),preferably saturated.

As used herein, "topical application" means directly laying on orspreading on outer skin.

As used herein, "pharmaceutically-acceptable" means that drugs,medicaments or inert ingredients which the term describes are suitablefor use in contact with the tissues of humans and lower animals withoutundue toxicity, incompatibility, instability, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio.

As used herein, "regulating wrinkles" means preventing, retarding,arresting, or reversing the process of wrinkle formation in mammalianskin.

As used herein, "skin atrophy" means the thinning and/or generaldegradation of the dermis often characterized by a decrease in collagenand/or elastin as well as decreased number, size and doubling potentialof fibroblast cells. Skin atrophy is a natural result of aging. Skinatrophy is often an undesirable side effect resulting from treatmentwith corticosteroids.

As used herein, "regulating skin atrophy" means preventing, retarding,arresting, or reversing the process of atrophy in mammalian skin.

As used herein, "safe and effective amount" means an amount of compoundor composition sufficient to significantly induce a positivemodification in the condition to be treated, but low enough to avoidserious side effects (at a reasonable benefit/risk ratio), within thescope of sound medical judgment. The safe and effective amount of thecompound or composition will vary with the particular condition beingtreated, the age and physical condition of the patient being treated,the severity of the condition, the duration of the treatment, the natureof concurrent therapy, the specific compound or composition employed,the particular pharmaceutically-acceptable carrier utilized, and likefactors within the knowledge and expertise of the attending physician.

As used herein, "chronic treatment" means continued treatment with anactive agent over an extended period during a subject's lifetime,preferably for at least about three weeks, more preferably from aboutthree months to about twenty years, more preferably from about sixmonths to about ten years, more preferably still from about one year toabout five years.

As used herein, all percentages are by weight unless otherwisespecified.

Active Compound

The present invention relates to a method for regulating wrinkles and/oratrophy in mammalian skin comprising treating the skin with a safe andeffective amount of a composition comprising an salicylic acid activecomponent. The salicylic acid active component can be salicylic acidalone, salicylic acid derivatives and salicylic acid in combination withother active ingredients described below. Most preferred is salicylicacid in a hydroalcoholic solution.

Salicylic acid is a well known active component and is generallydescribed in U.S. Pat. No. 4,514,385, to Damani, et al., assigned toAlcon Laboratories, issued Apr. 30, 1985.

The preferred topical carrier comprises a hydroalcoholic solution at pH2 to 4 of salicylic acid as the active anti-acne ingredient togetherwith a specific anionic surfactant component. More preferably suchactive is a stable, hydroalcoholic composition having a pH value of from2 to 4 and containing from about 0.2 to about 5.0 percent by weight ofsalicylic acid and from about 0.2 to about 5.0 percent by weight ofsodium methyl cocoyl taurate and/or sodium methyl oleoyl taurate as theanionic surfactant component. Generally, a sufficient amount of acosmetically acceptable alkaline component (i.e., alkalizing agent) toprovide and maintain the composition with a pH from about 2.0 to about 4is included.

As the alcohol component of the hydroalcoholic solvent, from about 10 toabout 60 percent by weight of ethyl alcohol, measured as total C₂ H₅ OHcontent, is preferred although a like amount of isopropyl alcohol (C₃ H₇OH) may also be beneficially utilized. From about 30 to about 80 percentby weight of water is also required as the aqueous component of thehydroalcoholic solvent.

The anionic surfactant component of this active composition, i.e., thetaurate surfactant component, is specifically directed to sodium methylcocoyl taurate and sodium methyl oleoyl taurate, both of which arereadily available from diverse commercial suppliers, as noted in TheCosmetic, Toiletry and Fragrance Association (CTFA) Cosmetic IngredientDictionary, 3rd Edition, 1982, pages 286-287.

Although it is preferred to use the taurate surfactant as the solesurfactant in the active compositions, other surfactants may beincluded, the nonionic type having preference over the anionic type inview of the relative non-irritating characteristic to the skin of theformer. Cationic type surfactants, which are most irritating to theskin, are less preferred because of their marked susceptibility tohydrolysis at the low acidic pH of the subject compositions.

The pH value of the preferred active component, from about 2 to about3.5, may be achieved by use of appropriate cosmetically acceptableprimary or dual buffer systems. In most instances, the resultant pH ofthe hydroalcoholic solution of salicylic acid is slightly below or atthe lower end of the indicated range, and all that is required to adjustthe pH to a desired higher value within the indicated range is to add analkaline additive such as is commonly utilized in cosmetic formulationsfor such purpose. Although sodium carbonate is preferred, other suitablealkalizing agents include potassium carbonate, sodium hydroxide,potassium hydroxide, triethanolamine and the like. If deemed necessaryto change or adjust the pH to a lower value, a suitable cosmeticallyacceptable acidifying agent such as citric acid may be employed.

Pharmaceutical Compositions

In a preferred embodiment, treatment will employ the use of a topicalpharmaceutical composition comprising the active compound and apharmaceutically-acceptable carrier. The term"pharmaceutically-acceptable carrier", as used herein, means one or morecompatible solid or liquid filler diluents or microencapsulatingsubstances which are suitable for administration to a human or loweranimal. Pharmaceutically-acceptable carriers must be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration to the human or lower animal being treated. A safe andeffective amount of carrier is from about 50% to about 99.99%,preferably from about 99.9% to about 80%, more preferably from about 98%to about 95%, of the composition.

Variations in formulation of these carriers will result in a widevariety of products which fall within the scope of the presentinvention.

The topical pharmaceutical compositions of the present invention may bemade into a wide variety of product types. These include, but are notlimited to solutions, lotions, creams, beach products, gels, sticks,sprays, pads, ointments, pastes, mousses and cosmetics. These producttypes may comprise several types of carrier systems including, but notlimited to solutions, emulsions, gels and solids.

The topical pharmaceutical compositions of the present inventionformulated as solutions typically include a pharmaceutically-acceptableaqueous or organic solvent. The terms "pharmaceutically-acceptableaqueous solvent" and "pharmaceutically-acceptable organic solvent" referto a solvent which is capable of having dispersed or dissolved thereinthe active compound, and possesses acceptable safety properties (e.g.,irritation and sensitization characteristics). Water is a typicalaqueous solvent. Examples of suitable organic solvents include:propylene glycol, butylene glycol, polyethylene glycol (200-600),polypropylene glycol (425-2025), glycerol, 1,2,4-butanetriol, sorbitolesters, 1,2,6-hexanetriol, ethanol, isopropanol, butanediol, andmixtures thereof. Preferably, these solutions contain from about 0.01%to about 50% of the active compound, more preferably from about 0.1% toabout 20%; and from about 1% to about 80% of an acceptable aqueous ororganic solvent, more preferably from about 1% to about 40%.

If the topical pharmaceutical compositions of the present invention areformulated as an aerosol and applied to the skin as a spray-on, apropellant is added to a solution composition. A more completedisclosure of propellants useful herein can be found in Sagarin,Cosmetics Science and Technology, 2nd Edition, Vol. 2, pp. 443-465(1972).

Topical pharmaceutical compositions of the present invention may beformulated as a solution comprising an emollient. An example of acomposition formulated in this way would be a sunscreen-containingproduct. Preferably, such compositions contain from about 0.1% to about50% of the active compound and from about 2% to about 50% of a topicalpharmaceutically-acceptable emollient.

As used herein, "emollients" refer to materials used for the preventionor relief of dryness, as well as for the protection of the skin. A widevariety of suitable emollients are known and may be used herein.Sagarin, Cosmetics Science and Technology, 2nd Edition, Vol. 1, pp.32-43 (1972), incorporated herein by reference, contains numerousexamples of suitable materials.

A lotion can be made from a solution carrier system. Lotions preferablycomprise from about 0.1% to about 20%, more preferably from about 1% toabout 5%, of the active compound; from about 1% to about 20%, preferablyfrom about 5% to about 10%, of an emollient; and from about 50% to about90%, preferably from about 60% to about 80%, water.

Another type of product that may be formulated from a solution carriersystem is a cream. A cream of the present invention would preferablycomprise from about 0.1% to about 20%, more preferably from about 1% toabout 5%, of the active compound; from about 5% to about 50%, preferablyfrom about 10% to about 20%, of an emollient, and from about 45% toabout 85%, preferably from about 50% to about 75%, water.

Yet another type of product that may be formulated from a solutioncarrier system is an ointment. An ointment may comprise a simple base ofanimal or vegetable oils or semi-solid hydrocarbons (oleaginous).Ointments may also comprise absorption ointment bases which absorb waterto form emulsions. Ointment carriers may also be water soluble. Anointment may also comprise from about 2% to about 10% of an emollientplus from about 0.1% to about 2% of a thickening agent. A more completedisclosure of thickening agents useful herein can be found in Segarin,Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. 72-73(1972).

If the carrier is formulated as an emulsion, from about 1% to about 10%,preferably from about 2% to about 5%, of the carrier system comprises anemulsifier. Emulsifiers may be nonionic, anionic or cationic. Suitableemulsifiers are disclosed in, for example, U.S. Pat. No. 3,755,560,issued Aug. 28, 1973, Dickert et al; U.S. Pat. No. 4,421,769, issuedDec. 20, 1983, Dixon et al.; and McCutcheon's Detergents andEmulsifiers, North American Edition, pages 317-324 (1986); thedisclosures of which are incorporated herein by reference. Preferredemulsifiers are anionic or nonionic, although the other types may alsobe used.

Lotions and creams can be formulated as emulsions as well as solutions.Preferably such lotions comprise from about 0.1% to about 20%, morepreferably from about 1% to about 5%, of the active compound; from about1% to about 20%, preferably from about 5% to about 10%, of an emollient;from about 25% to about 75%, preferably from about 45% to about 95%,water; and from about 0.1% to about 10%, preferably from about 0.5% toabout 5%, of an emulsifier. Such creams would preferably comprise fromabout 0.1% to about 20%, more preferably from about 1% to about 5%, ofthe active compound; from about 1% to about 20%, preferably from about5% to about 10%, of an emollient; from about 20% to about 80%,preferably from about 30% to about 70%, water; and from about 1% toabout 10%, preferably from about 2% to about 5%, of an emulsifier.

Single emulsion skin care preparations, such as lotions and creams, ofthe oil-in-water type and water-in-oil type are well-known in thecosmetic art and are useful in the present invention. Multiphaseemulsion compositions, such as the water-in-oil-in-water type, asdisclosed in U.S. Pat. No. 4,254,105, Fakuda et al., issued Mar. 3,1981, incorporated herein by reference, are also useful in the presentinvention. In general, such single or multiphase emulsions containwater, emollients and emulsifiers as essential ingredients.

Triple emulsion carrier systems comprising an oil-in-water-in-siliconefluid emulsion composition as disclosed in U.S. Pat. No. 4,960,764,Figueroa, issued Oct. 2, 1990, are also useful in the present invention.Preferably, this triple emulsion carrier system can be combined withfrom about 0.1% to about 20%, more preferably from about 1% to about 5%,of the active compound to yield the topical pharmaceutical compositionof the present invention.

Another emulsion carrier system useful in the topical pharmaceuticalcompositions of the present invention is a micro-emulsion carriersystem. Such a system comprises from about 9% to about 15% squalane;from about 25% to about 40% silicone oil; from about 8% to about 20% ofa fatty alcohol; from about 15% to about 30% of polyoxyethylene sorbitanmono-fatty acid (commercially available under the trade name Tweens) orother nonionics; and from about 7% to about 20% water. This carriersystem is preferably combined with from about 1% to about 5% of theactive compound.

If the topical pharmaceutical compositions of the present invention areformulated as a gel or a cosmetic stick, a suitable amount of athickening agent, as disclosed supra, is added to a cream or lotionformulation.

The topical pharmaceutical compositions of the present invention mayalso be formulated as makeup products such as foundations.

The topical pharmaceutical compositions of the present invention mayalso be formulated as medicated pads. Suitable examples of these padsare fully disclosed in U.S Pat. Nos. 4,891,227 and 4,891,228, to Thamanet al., both issued Jan. 2, 1990 the disclosures of which areincorporated herein.

The topical pharmaceutical compositions of the present invention maycontain, in addition to the aforementioned components, a wide variety ofadditional oil-soluble materials and/or water-soluble materialsconventionally used in topical compositions, at their art-establishedlevels.

Various water-soluble materials may also be present in the compositionsof this invention. These include humectants, proteins and polypeptides,preservatives and an alkaline agent. In addition, the topicalcompositions herein can contain conventional cosmetic adjuvants, such asdyes, opacifiers (e.g., titanium dioxide), pigments and perfumes.

The topical pharmaceutical compositions of the present invention mayalso include a safe and effective amount of a penetration enhancingagent. A preferred amount of penetration enhancing agent is from about1% to about 5% of the composition. Another useful penetration enhancerfor the present invention is the non-ionic polymer under the CTFAdesignation: polyacrylamide and isoparrafin and laureth-7, available asSepigel from Seppic Corporation. Also useful is polyquaternium-32 andmineral oil known as SalCare SC92 available from Allied Colloids,Suffolk, Va. This is a class of cationic polymers which are generallydescribed in U.S. Pat. No. 4,628,078 to Glover et al. issued Dec. 9,1986 and U.S. Pat. No. 4,599,379 to Flesher et al. issued Jul. 8, 1986both of which are incorporated by reference herein.

Examples of useful penetration enhancers, among others, are disclosed inU.S. Pat. No. 4,537,776, Cooper, issued Aug. 27, 1985; U.S. Pat. No.4,552,872, Cooper et al., issued Nov. 12, 1985; U.S. Pat. No. 4,557,934,Cooper, issued Dec. 10, 1985; U.S. Pat. No. 4,130,667, Smith, issuedDec. 19, 1978; U.S. Pat. No. 3,989,816, Rhaadhyaksha, issued Nov. 2,1976; U.S. Pat. No. 4,017,641, DiGiulio, issued Apr. 12, 1977; andEuropean Patent Application 0043738, Cooper et al., published Jan. 13,1982.

Other conventional skin care product additives may also be included inthe compositions of the present invention. For example, collagen,hyaluronic acid, elastin, hydrolysates, primrose oil, jojoba oil,epidermal growth factor, soybean saponins, mucopolysaccharides, andmixtures thereof may be used.

Vitamins

Various vitamins may also be included in the compositions of the presentinvention. For example, Vitamin A, ascorbic acid, Vitamin B, biotin,panthothenic acid, Vitamin D, Vitamin E and mixtures thereof andderivatives thereof may be used.

Cleaning Compositions

The skin cleaning compositions of the present invention comprise, inaddition to the active compound, a cosmetically-acceptable surfactant.The term "cosmetically-acceptable surfactant" refers to a surfactantwhich is not only an effective skin cleanser, but also can be usedwithout undue toxicity, irritation, allergic response, and the like.Furthermore., the surfactant must be capable of being commingled withthe active compound in a manner such that there is no interaction whichwould substantially reduce the efficacy of the composition forregulating skin wrinkles and/or skin atrophy.

The skin cleaning compositions of the present invention preferablycontain from about 0.1% to about 20%, preferably from about 1% to about5%, of the active compound and from about 1% to about 90%, morepreferably from about 1% to about 10%, of a cosmetically-acceptablesurfactant.

The physical form of the skin cleansing compositions is not critical.The compositions can be, for example, formulated as toilet bars,liquids, pastes, mousses, or pads.

The surfactant component of the compositions of the present inventionare selected from anionic, nonionic, zwitterionic, amphoteric andampholytic surfactants, as well as mixtures of these surfactants. Suchsurfactants are well-known to those skilled in the detergency art.

The cleaning compositions of the present invention can optionallycontain, at their art-established levels, materials which areconventionally used in skin cleansing compositions.

Combination Actives

A. Sunscreens and Sunblocks

Optimum regulation of skin wrinkling resulting from exposure to U.V.light can be obtained by using a combination of the salicylic acidactive of the present invention together with sunscreens or sunblocks.Useful sunblocks include, for example, zinc oxide and titanium dioxide.

Photodamage is a predominant cause of skin wrinkling. Thus, for purposesof wrinkle prevention, the combination of the active compound with a UVAand/or UVB sunscreen would be most desirable. The inclusion ofsunscreens in compositions of the present invention will provideimmediate protection against acute UV damage. Thus, the sunscreen willprevent further wrinkle formation caused by UV radiation, while theactive compound regulates existing wrinkles and skin atrophy.

A wide variety of conventional sunscreening agents are suitable for usein combination with the active compound. Segarin, et al., at ChapterVIII, pages 189 et seq., of Cosmetics Science and Technology, disclosenumerous suitable agents. Specific suitable sunscreening agents include,for example: p-aminobenzoic acid, its salts and its derivatives (ethyl,isobutyl, glyceryl esters; p-dimethylaminobenzoic acid); anthranilates(i.e., o-aminobenzoates; methyl, menthyl, phenyl, benzyl, phenylethyl,linalyl, terpinyl, and cyclohexenyl esters); salicylates (amyl, phenyl,benzyl, menthyl, glyceryl, and dipropyleneglycol esters); cinnamic acidderivatives (methyl and benzyl esters, α-phenyl cinnamonitrile; butylcinnamoyl pyruvate); Dihydroxycinnamic acid derivatives (umbelliferone,methylumbelliferone, methylaceto-umbelliferone); trihydroxycinnamic acidderivatives (esculetin, methylesculetin, daphnetin, and the glucosides,esculin and daphnin); hydrocarbons (diphenylbutadiene, stilbene);dibenzalacetone and benzalacetophenone; Naphtholsulfonates (sodium saltsof 2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids);Dihydroxy-naphthoic acid and its salts; o- andp-Hydroxybiphenyldisulfonates; Coumarin derivatives (7-hydroxy,7-methyl, 3-phenyl); Diazoles (2-acetyl -3-bromoindazole, phenylbenzoxazole, methyl naphthoxazole, various aryl benzothiazoles); Quininesalts (bisulfate, sulfate, chloride, oleate, and tannate); Quinolinederivatives (8-hydroxyquinoline salts, 2-phenylquinoline); Hydroxy- ormethoxy-substituted benzophenones; Uric and vilouric acids; Tannic acidand its derivatives (e.g., hexaethylether); (Butyl carbotol) (6-propylpiperonyl) ether; Hydroquinone; Benzophenones (Oxybenzene,Sulisobenzone, Dioxybenzone, Benzoresorcinol,2,2',4,4'-Tetrahydroxybenzophenone,2,2'-Dihydroxy-4,4'-dimethoxybenzophenone, Octabenzone;4-Isopropyldibenzoylmethane; Butylmethoxydibenzoylmethane; Etocrylene;and 4- isopropyl-di-benzoylmethane.

Preferred sunscreens useful in the compositions of the present inventionare 2-ethylhexyl-p-methoxycinnamate, butyl-methoxydibenzoylmethane,2-hydroxy-4-methoxybenzophenone, octyl-dimethyl-p-aminobenzoic acid andmixtures thereof.

A safe and effective amount of sunscreen may be used in the compositionsof the present invention. The sunscreening agent must be compatible withthe active compound. Generally the composition may comprise from about1% to about 20%, preferably from about 2% to about 10%, of asunscreening agent. Exact amounts will vary depending upon the sunscreenchosen and the desired Sun Protection Factor (SPF).

Also particularly useful in the present invention are sunscreens such asthose disclosed in Sabatelli, U.S. patent application Ser. No. 054,085(filed Jun. 2, 1987) and Sabatelli et al., U.S. patent application Ser.No 054,046 (filed Jun. 2, 1987). The sunscreening agents disclosedtherein have, in a single molecule, two distinct chromophore moletieswhich exhibit different ultra-violet radiation absorption spectra. Oneof the chromophore moieties absorbs predominantly in the UVB radiationrange and the other absorbs strongly in the UVA radiation range.

An agent may also be added to any of the compositions of the presentinvention to improve the skin substantivity of those compositions,particularly to enhance their resistance to being washed off by water,or rubbed off. A preferred agent which will provide this benefit is acopolymer of ethylene and acrylic acid. Compositions comprising thiscopolymer are disclosed in U.S. Pat. No. 4,663,157, Brock, issued May 5,1987, which is incorporated herein by reference.

B. Anti-Inflammatory Agents

In a preferred wrinkle and atrophy regulating composition of the presentinvention, an anti-inflammatory agent is included as an active agentalong with the active compound. The inclusion of an anti-inflammatoryagent enhances the wrinkle regulating benefits of the compositions. Theanti-inflammatory agent protects strongly in the UVA radiation range(though it also provides some UVB protection as well) thereby preventingfurther wrinkle formation caused by UV radiation, while the activecompound regulates existing wrinkles and skin atrophy. Thus thecombination provides broad protection. The topical use ofanti-inflammatory agents reduces photo-aging of the skin resulting fromchronic exposure to UV radiation. (See U.S. Pat. No. 4,847,071, Bissett,Bush, and Chatterjee, issued Jul. 11, 1989, incorporated herein byreference; and U.S. Pat. No. 4,847,069, Bissett and Chatterjee, issuedJul. 11, 1989, incorporated herein by reference.)

A safe and effective amount of an anti-inflammatory agent may be addedto the compositions of the present invention, preferably from about 0.1%to about 10%, more preferably from about 0.5% to about 5%, of thecomposition. The exact amount of anti-inflammatory agent to be used inthe compositions will depend on the particular anti-inflammatory agentutilized since such agents vary widely in potency.

Steroidal anti-inflammatory agents, including but not limited to,corticosteroids such as hydrocortisone, hydroxyltriamcinolone,alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasonedipropionate, clobetasol valerate, desonide, desoxymethasone,desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasonediacetate, diflucortolone valerate, fluadrenolone, flucloroloneacetonide, fludrocortisone, flumethasone pivalate, fluosinoloneacetonide, fluocinonide, flucortine butylester, fluocortolone,fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide,hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone,triamcinolone acetonide, cortisone, cortodoxone, flucetonide,fludrocortisone, difluorosone diacetate, fluradrenolone acetonide,medrysone, amcinafel, amcinafide, betamethasone and the balance of itsesters, chloroprednisone, chlorprednisone acetate, clocortelone,clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide,fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate,hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone,paramethasone, prednisolone, prednisone, beclomethasone dipropionate,triamcinolone, and mixtures thereof may be used. The preferred steroidalanti-inflammatory for use in the present invention is hydrocortisone.

A second class of anti-inflammatory agents which is useful in thecompositions of the present invention includes the nonsteroidalanti-inflammatory agents. The variety of compounds encompassed by thisgroup are well-known to those skilled in the art. For detaileddisclosure of the chemical structure, synthesis, side effects, etc., ofnon-steroidal anti-inflammatory agents, reference may be had to standardtexts, including Antiinflammatory and Anti-Rheumatic Drugs, K. D.Rainsford, Vol. I-III, CRC Press, Boca Raton, (1985), andAnti-inflammatory Agents, Chemistry and Pharmacology, 1, R. A. Scherrer,et al., Academic Press, New York (1974).

Specific non-steroidal anti-inflammatory agents useful in thecomposition of the present invention include, but are not limited to:

1) the oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, andCP-14,304;

2) the salicylates, such as aspirin, disalcid, benorylate, trilisate,safapryn, solprin, diflunisal, and fendosal;

3) the acetic acid derivatives, such as diclofenac, fenclofenac,indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac,zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, andfelbinac;

4) the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic,and tolfenamic acids;

5) the propionic acid derivatives, such as ibuprofen, naproxen,benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen,indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and

6) the pyrazoles, such as phenybutazone, oxyphenbutazone, feprazone,azapropazone, and trimethazone.

Mixtures of these non-steroidal anti-inflammatory agents may also beemployed, as well as the pharmaceutically-acceptable salts and esters ofthese agents. For example, etofenamate, a flufenamic acid derivative, isparticularly useful for topical application. Of the nonsteroidalanti-inflammatory agents, ibuprofen, naproxen, flufenamic acid,mefenamic acid, meclofenamic acid, piroxicam and felbinac are preferred;ibuprofen, naproxen, and flufenamic acid are most preferred.

Another class of anti-inflammatory agents which are useful in thepresent invention are the anti-inflammatory agents disclosed in U.S.Pat. No. 4,708,966, Loomans et al., issued Nov. 24, 1987. This patentdiscloses a class of nonsteroidal anti-inflammatory compounds whichcomprise specifically substituted phenyl compounds, especiallysubstituted 2,6-di- tert-butyl phenol derivatives. For example,compounds selected from 4 -(4'-pentyn-3'-one)-2,6-di-t-butylphenol;4-(5'-hexynoyl)-2,6-di-t-butylphenol;4-((S)-(-)-3'-methyl-5'-hexynoyl)-2,6-di-t-butylphenol;4-((R)-(+)-3'-methyl-5'-hexynoyl)-2,6-di-t-butylphenol; and4-(3',3'-dimethoxypropionyl)-2,6-di-t-butylphenol are useful in thepresent invention.

Yet another class of anti-inflammatory agents which are useful in thepresent invention are those disclosed in U.S. Pat. No. 4,912,248,Mueller, issued Mar. 27, 1990. This patent discloses compounds anddiastereomeric mixtures of specific 2-naphthyl containing estercompounds, especially naproxen ester and naproxol ester compounds,having two or more chiral centers.

Finally, so-called "natural" anti-inflammatory agents are useful in thepresent invention. For example, candelilla wax, alpha bisabolol, aloevera, Manjistha (extracted from plants in the genus Rubia, particularlyRubia Cordifolia), and Guggal (extracted from plants in the genusCommiphora, particularly Commiphora Mukul), may be used.

C. Anti-Oxidants/Radical Scavengers

In a preferred wrinkle and atrophy regulating composition of the presentinvention, an anti-oxidant/radical scavenger is included as an activeagent along with the active compound. The inclusion of ananti-oxidant/radical scavenger increases the wrinkle regulating benefitsof the composition.

A safe and effective amount of an anti-oxidant/radical scavenger may beadded to the compositions of the present invention, preferably fromabout 0.1% to about 10%, more preferably from about 1% to about 5%, ofthe composition.

Anti-oxidants/radical scavengers such as ascorbic acid (vitamin C) andits salts, tocopherol (vitamin E), tocopherol sorbate, other esters oftocopherol, butylated hydroxy benzoic acids and their salts,6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commerciallyavailable under the tradename Trolox®), gallic acid and its alkylesters, especially propyl gallate, uric acid and its salts and alkylesters, sorbic acid and its salts, the ascorbyl esters of fatty acids,amines (e.g., N,N-diethylhydroxylamine, amino-guanidine), sulfhydrylcompounds (e.g., glutathione), and dihydroxy fumaric acid and its saltsmay be used.

D. Chelators

In a preferred wrinkle and atrophy regulating composition of the presentinvention, a chelating agent is included as an active agent along withthe active compound. As used herein, "chelating agent" means an activeagent capable of removing a metal ion from a system by forming a complexso that the metal ion cannot readily participate in or catalyze chemicalreactions. The inclusion of a chelating agent increases the wrinkleregulating benefits of the composition.

A safe and effective amount of a chelating agent may be added to thecompositions of the present invention, preferably from about 0.1% toabout 10%, more preferably from about 1% to about 5%, of thecomposition. Chelators useful in compositions of the present inventionare disclosed in U.S. patent application Ser. No. 251,910, Bissett, Bush& Chatterjee, filed Oct. 4, 1988, incorporated herein by reference.Preferred chelators useful in compositions of the present invention arefurildioxime and derivatives thereof, more preferablyamphi-2-furildioxime.

E. Retinoids

In a preferred wrinkle and atrophy regulating composition of the presentinvention, a retinoid, preferably retinoic acid, is included as anactive agent along with the active compound. The inclusion of a retinoidincreases the wrinkle regulating benefits of the composition. A safe andeffective amount of a retinoid may be added to the compositions of thepresent invention, preferably from about 0.001% to about 2%, morepreferably from about 0.01% to about 1% of the composition. As usedherein, "retinoid" includes all natural and/or synthetic analogs ofVitamin A or retinol-like compounds which possess the biologicalactivity of Vitamin A in the skin as well as the geometric isomers andstereoisomers of these compounds, such as all-trans retinoic acid and13-cis-retinoic acid.

F. Benzofuran Derivatives

In a preferred wrinkle and atrophy regulating composition of the presentinvention, a benzofuran derivative, preferably amiodarone, is includedas an active agent along with the active compound. The inclusion of abenzofuran derivative increases the wrinkle regulating benefits of thecomposition.

A safe and effective amount of a benzofuran derivative may be added tothe compositions of the present invention, preferably from about 0.01%to about 20%, more preferably from about 0.1% to about 10%, of thecomposition. Benzofuran derivatives useful in the present invention aredisclosed in U.S. patent application Ser. No. 674,628, Chatterjee andKapoor, filed Mar. 25, 1991, incorporated herein by reference.

G. N-acetyl-L-cysteine Derivatives

Also preferred for use herein are compounds having the structure##STR1## or a pharmaceutically-acceptable salt thereof.

R¹ is selected from the group consisting of nil and a C₁ -C₁₈ alkyl,preferably C₁ -C₇, more preferably C₁ -C₃, more preferably still C₁alkyl.

R² is selected from the group consisting of nil, --H, C₁ -C₁₈ alkyl and##STR2## preferably --H and, C₁ -C₁₈ alkyl, more preferably --H. In oneembodiment, R² is preferably a C₁ -C₁₈ alkyl, more preferably C₁ -C₇,more preferably C₁ -C₃, more preferably still C₁.

R³ is selected from the group consisting of --H, and C₁ -C₁₈ alkylpreferably --H. In one embodiment, R³ is preferably a C₁ -C₁₈ alkyl,more preferably C₁ -C₇, more preferably C₁ -C₃, more preferably stillC₁.

R⁴ is a C₁ -C₁₈ alkyl; preferably C₁ -C₇ ; more preferably C₁ -C₃ ; morepreferably still C₁.

In another embodiment, both R¹ and R² are nil and the carbonyl carbonand the sulfur adjacent R¹ and R², respectively, are covalently bondedto form a cyclic ring. Otherwise, both R¹ and R² are other than nil.

Preferred pharmaceutically-acceptable salts of the active compoundinclude, but are not limited to, sodium, potassium, magnesium, calcium,lithium, rubidium, strontium, aluminum, boron, silicon and zinc salts ofthe active compound.

Compositions of the present invention comprise from about 0.01% to about50% of the active compound, preferably from about 0.1% to about 20%,more preferably from about 2% to about 5%.

Zinc complexes which may be formed by zinc and the active compound areuseful in the compositions and methods of the present invention.

H. Skin Protectants

In a preferred wrinkle and atrophy regulating composition of the presentinvention, a safe and effective amount of a skin protectant may be addedto the compositions of the present invention, the skin protectantpreferably comprises from about 0.001% to about 2%, more preferably fromabout 0.01% to about 1% of the composition. Useful skin protectants aredisclosed in the Federal Register Vol. 48, No. 32 and include allantoin,aluminum hydroxide gel, bismuth subnitrate, boric acid, calamine, cocoabutter, corn starch, dimethicone, glycerin, kaolin, live yeast cellderivative, petrolatum, shark liver oil, sodium bicarbonate, sulfur,tannic acid, white petrolatum, zinc acetate, zinc carbonate and zincoxide and mixtures thereof.

Other useful components include hormones such as pregnenolone andestrogens. Also useful are the alpha-, or beta-hydroxy acids oralpha-keto acids or derivatives thereof as disclosed in U.S. Pat. No.4,234,599 to Van Scott et al., issued Nov. 18, 1980 which isincorporated by reference herein. Useful members of this class includealpha-hydroxy-butyric acid, alpha-hydroxyisobutyric acid,alpha-hydroxyisocaproic acid, alpha-hydroxyisovaleric, atrolactic acid,beta-hydroxybutyric acid, beta-phenyl lactic acid, beta-phenylpyruvicacid, citric acid ethyl pyruvate, galacturonic acid, glucoheptonic acid,glucoheptono 1,4-lactone, gluconic acid, gluconolactone glucuronic acid,glucuronolactone, glycolic acid, isopropyl pyruvate, lactic acid, malicacid, amndelic acid, emthyl pyruvate, mucic acid, pyruvic acid,saccharic acid, saccharic acid 1,4-lactone, tartaric acid and tartronicacid.

Methods for Regulating Wrinkles and/or Skin Atrophy in Mammalian Skin

The present invention relates to a method for regulating wrinkles and/oratrophy in mammalian skin. Such a method comprises treating the skinwith a safe and effective amount of the active compound. The amount ofactive compound and frequency of treatment will vary widely dependingupon the level of wrinkling and/or skin atrophy already in existence inthe subject, the rate of further wrinkle formation and/or atrophy, andthe level of regulation desired.

A preferred method of treating the skin is via chronic topicalapplication of a safe and effective amount of the active compound toregulate wrinkles and/or atrophy in mammalian skin. The amount of activecompound and frequency of topical application to the skin can varywidely, depending upon personal needs, but it is suggested as an examplethat topical application range from about once per week to about 10times daily, preferably from about twice per week to about 4 timesdaily, more preferably from about 3 times a week to about 3 times daily,most preferably about once or twice per day. The composition for topicalapplication will comprise from about 0.01% to about 50%, preferably fromabout 0.1% to about 20%, more preferably from about 1% to about 5% ofthe active compound. By "chronic" application, it is meant herein thatthe period of topical application may be over the lifetime of thesubject, preferably for a period of at least about three weeks, morepreferably from about three months to about twenty years, morepreferably from about six months to about ten years, more preferablystill from about one year to about five years, thereby resulting inregulation of wrinkles and/or atrophy in mammalian skin.

A preferred method of the present invention for regulating wrinklesand/or atrophy in mammalian skin involves applying both a safe andeffective amount of the active compound and a safe and effective amountof one or more of a sunscreening agent, anti-inflammatory agent,Vitamin, anti-oxidant/radical scavenging agent, chelating agent,retinoid, N-acetyl-L-cysteine derivative, skin protectant and/orbenzofuran derivative to the skin simultaneously. As used herein,"simultaneous application" or "simultaneously" means applying the agentsto the skin at the same situs on the body at about the same time. Thoughthis can be accomplished by applying the agents separately to the skin,preferably a composition comprising all the desired agents commingled isapplied to the skin. The amount of sunscreening agent applied isgenerally from about 0.02 mg to about 1.0 mg per cm² skin. The amount ofanti-inflammatory agent applied is generally from about 0.005 mg toabout 0.5 mg, preferably from about 0.01 mg to about 0.1 mg per cm²skin. The amount of anti-oxidant/radical scavenging agent generallyapplied is from about 0.001 mg to about 1.0 mg, preferably from about0.05 mg to about 0.5 mg per cm² skin. The amount of chelating agentgenerally applied is from about 0.001 mg to about 1.0 mg, preferablyfrom about 0.01 mg to about 0.5 mg, more preferably from about 0.05 mgto about 0.1 mg per cm² skin. The amount of retinoid applied isgenerally from about 0.00001 mg to about 0.02 mg per cm² skin,preferably from about 0.001 mg to about 0.01 mg per cm² skin. The amountof benzofuran derivative applied is generally from about 0.001 mg toabout 1.0 mg/cm² skin per application, preferably from about 0.01 toabout 0.5 mg/cm² skin per application. The amount of active compoundapplied is generally from about 0.001 mg to about 1.0 mg per cm² skinper application, preferably from about 0.01 mg to about 0.5 mg per cm²,more preferably from about 0.05 to about 0.25 mg/cm² skin perapplication.

In a preferred wrinkle regulating composition of the present invention,compositions comprise one, a combination or all of a sunscreening agent,anti-inflammatory agent, Vitamin, anti-oxidant/radical scavenging agent,chelating agent, retinoid, N-acetyl-L-cysteine derivative, skinprotectant and/or benzofuran derivative included as actives along withthe active compound. The inclusion of any, a combination or all of theseagents with the active compound increases the wrinkle regulatingbenefits of the composition.

The following examples further describe and demonstrate the preferredembodiments within the scope of the present invention. The examples aregiven solely for the purpose of illustration, and are not to beconstrued as limitations of the present invention since many variationsthereof are possible without departing from its spirit and scope.

EXAMPLE I

A pad of the present invention is made as follows:

    ______________________________________                                                          Weight %                                                    ______________________________________                                        Pad Composition                                                               Substrate A                                                                   Cellulose-based nonwoven.sup.1                                                                    100.0                                                     Substrate B                                                                   Polyester (denier = 6).sup.2                                                                      45.0                                                      Orlon (denier = 8).sup.3                                                                          15.0                                                      Styrene-butadiene resin.sup.4                                                                     40.0                                                      Laminate                                                                      Polyethylene Powder Melt.sup.5                                                                    100.0                                                     Active Composition                                                            Salicylic acid      2.0                                                       Na Methyl cocoyl taurate                                                                          3.0                                                       C.sub.2 H.sub.5 OH (95% ethanol)                                                                  35.0                                                      Witch Hazel distillate                                                                            5.0                                                       Quaternium-22       1.0                                                       Menthol             0.1                                                       Aloe Vera Gel       0.5                                                       Fragrance           0.05                                                      Water               q.s.                                                      ______________________________________                                         .sup.1 Obtained from James River as Airtex Spec 382.                          .sup.2 Obtained from Eastern Chemical Company.                                .sup.3 Obtained from American Cyanamid.                                       .sup.4 Obtained from Reichold as tylac 68-500 (ratio of styrene to            butadiene 80:20).                                                             .sup.5 Obtained from Quantum Chemical as microthene powder.              

Substrate A has a basis weight of about 55 grams per square yard and aloft of about 35 mills. Substrate B has a basis weight of about 65 gramsper square yard and a loft of about 70 to 80 mills. The two materialsare laminated together by applying a thin coat of Polyethylene power toSubstrate A and heating with IR lamps. Substrate A and B are then joinedat a hip roll to compress and bond the materials. The resulting nonwovenfabric has a loft of about 90 to 100 mills. The resulting material isthen cut into an oval shape (5 cm.×7 cm.). The active components arecombined to form a solution and the pad composition is saturated in thissolution.

This composition is useful for topical application to regulate skinwrinkles and/or skin atrophy. Use of an amount of the composition todeposit about 2 mg/cm² of the active compound to the skin isappropriate.

EXAMPLE II

A pad of the present invention is made by combining the followingcomponents as in Example I:

    ______________________________________                                                          Weight %                                                    ______________________________________                                        Pad Composition                                                               Substrate A                                                                   Cellulose-based nonwoven                                                                          100.0                                                     Substrate B                                                                   Polyester (denier = 6)                                                                            45.0                                                      Orlon (denier = 8)  15.0                                                      Styrene-butadiene resin                                                                           40.0                                                      Laminate                                                                      Polyethylene Powder Melt                                                                          100.0                                                     Active Composition                                                            Salicylic acid      2.0                                                       C.sub.2 H.sub.5 OH (95% ethanol)                                                                  35.0                                                      Glycerin            2.0                                                       Aloe Vera Gel       1.0                                                       Menthol             0.05                                                      Triethanol Amine    0.7                                                       Fragrance           0.15                                                      Water               q.s.                                                      ______________________________________                                    

This composition is useful for topical application to regulate skinwrinkles and/or skin atrophy. Use of an amount of the composition todeposit about 2 mg/cm² of the active compound to the skin isappropriate.

EXAMPLE III

A topical composition is prepared by combining the following componentsutilizing conventional mixing techniques.

    ______________________________________                                        Active Composition Weight %                                                   ______________________________________                                        Salicylic acid     1.25                                                       Ascorbic acid      5.00                                                       Na Methyl cocoyl taurate                                                                         1.5                                                        C.sub.2 H.sub.5 OH (95% ethanol)                                                                 45.0                                                       Witch Hazel distillate                                                                           5.0                                                        Quaternium-22      1.0                                                        Menthol            0.05                                                       Fragrance          0.05                                                       Water              41.15                                                      ______________________________________                                    

This composition is useful for topical application to regulate skinwrinkles and/or skin atrophy. Use of an amount of the composition todeposit about 2 mg/cm² of the active compound to the skin isappropriate.

EXAMPLE IV

A topical composition is made by combining the following componentsusing conventional mixing technology.

    ______________________________________                                        Ingredient         W/W%                                                       ______________________________________                                        Water, Purified    54.0                                                       Alcohol SD 40      40.0                                                       Polyacrylamide and C.sub.13-14                                                                   4.0                                                        Isoparaffin and Laureth-7.sup.1                                               Salicylic Acid     2.0                                                        ______________________________________                                         .sup.1 Available as Sepigel from Seppic Corporation.                     

Water is added to a suitable size container. While mixing at a moderatespeed (300 rpm), the polyacrylamide isoparaffin and laureth-7 is addedto the water. Separately, the alcohol is placed in a container andcovered. Using a Lightnin' Mixer with a 3 blade paddle prop, thesalicylic acid is added to the alcohol and mixed at a low speed (100rpm) until all salicylic acid is dissolved. The alcohol is slowly addedto the water phase to form a gel. The resulting gel is mixed at moderatespeed until uniform.

This composition is useful for topical application to regulate skinwrinkles and/or skin atrophy. Use of an amount of the composition todeposit about 2 mg/cm² of the active compound to the skin isappropriate.

EXAMPLE V

A topical composition is made by combining the following componentsusing conventional mixing technology as in Example IV.

    ______________________________________                                        Ingredient      W/W%                                                          ______________________________________                                        Water           q.s.                                                          Alcohol SD 40   40.0                                                          Salcare SC92.sup.1                                                                            3.0                                                           Salicylic Acid  2.0                                                           Menthol         0.05                                                          N.sub.92 EDTA   0.05                                                          Glycerin        2.00                                                          ______________________________________                                    

This composition is useful for topical application to regulate skinwrinkles and/or skin atrophy. Use of an amount of the composition todeposit about 2 mg/cm² of the active compound to the skin isappropriate.

What is claimed is:
 1. A method for preventing, retarding, arresting, orreversing wrinkles or atrophy in mammalian skin comprising treating theskin with a safe and effective amount of a composition comprising:(a) asafe and effective amount of salicylic acid; (b) a safe and effectiveamount of a retinoid selected from the group consisting of all-transretinoic acid, 13-cis-retinoic acid, Vitamin A, natural or syntheticanalogs of Vitamin A, and mixtures thereof; and (c) apharmaceutically-acceptable carrier.